High speed/high capacity railway and regional development - evaluation of effects on spatial accessibility

In the last decade the theme of high speed infrastructure in Italy has been deeply debated, with different political and technical opinions, which have expanded the time for projects and constructions. As a consequence of this long debate, a redefinition of the whole system, moving from high speed to high speed/high capacity railway system (HS/HC) has been agreed. This new model can be considered more suitable especially for the northern Italy corridor, which is highly populated and densely urbanised. Moreover, while the environmental effects of transportation facilities and of high speed infrastructure are relatively well known in literature since the Environmental Impact Assessment (EIA) procedure has been applied to several study cases, the effects on economical and geographical structure are less studied and so quite often misunderstood or underestimated. According to a demand-side approach, infrastructure investments will follow mobility needs by the economical system, while from a supply-side approach infrastructure are a crucial means of regional growth. This paper presents a study case in northern Italy (the Milan-Verona track, of about 140 km of lenght), and it shows how spatial effect of a transport network can spread off far from the line, determining a new regional hierarchy and new location opportunity in a wide and highly populated area. A comparison has been made between the original high speed model and the most recent high speed-high capacity model. In the two cases the work investigates what is the area where the new infrastructure shows effects, at short and long term. With a spatial interaction model, used to represent residential location in relation to the distribution of workplaces, HS/HC line efficiency by accessibility calculus has been measured, showing several important results. Those results may be of interest even in similar European context where the HS programme is developing.

Distinct populations of neurons activated by heroin and cocaine in the striatum as assessed by catFISH

Despite the still prevailing notion of a shared substrate of action for all addictive drugs, there is evidence suggesting that opioid and psychostimulant drugs differ substantially in terms of their neurobiological and behavioural effects. These differences may reflect separate neural circuits engaged by the two drugs. Here we used the catFISH technique to investigate the degree of overlap between neurons engaged by heroin versus cocaine in adult male Sprague-Dawley rats. The catFISH technique is a within-subject procedure that takes advantage of the different transcriptional time-course of the immediate-early genes homer 1a and arc to determine to what extent two stimuli separated by an interval of 25 min engage the same neuronal population. We found that throughout the striatal complex the neuronal populations activated by non-contingent intravenous injections of cocaine (800 µg/kg) and heroin (100 and 200 µg/kg), administered at an interval of 25 min from each other, overlapped to a much lesser extent than in the case of two injections of cocaine (800 µg/kg), also 25 min apart. The greatest reduction in overlap between populations activated by cocaine and heroin was in the dorsomedial and dorsolateral striatum (~30% and ~22%, respectively, of the overlap observed for the sequence cocaine-cocaine). Our results point toward a significant separation between neuronal populations activated by heroin and cocaine in the striatal complex. We propose that our findings are a proof of concept that these two drugs are encoded differently in a brain area believed to be a common neurobiological substrate to drug abuse

Cardiovascular and hepatic toxicity of cocaine: potential beneficial effects of modulators of oxidative stress

Oxidative stress (OS) is thought to play an important role in the pharmacological and toxic effects of various drugs of abuse. Herein we review the literature on the mechanisms responsible for the cardiovascular and hepatic toxicity of cocaine with special focus on OS-related mechanisms. We also review the preclinical and clinical literature concerning the putative therapeutic effects of OS modulators (such as N-acetylcysteine, superoxide dismutase mimetics, nitroxides and nitrones, NADPH oxidase inhibitors, xanthine oxidase inhibitors, and mitochondriotropic antioxidants) for the treatment of cocaine toxicity. We conclude that available OS modulators do not appear to have clinical efficacy

Role of Echocardiography Before Transcatheter Aortic Valve Implantation (TAVI)

Aortic stenosis (AS) is the most common primary valve disorder in the elderly with an increasing prevalence; transcatheter aortic valve implantation (TAVI) has become an accepted alternative to surgical aortic valve replacement (AVR) in the high risk or inoperable patient. Appropriate selection of patients for TAVI is crucial and requires a multidisciplinary approach including cardiothoracic surgeons, interventional cardiologists, anaesthetists, imaging experts and specialist nurses. Multimodality imaging including echocardiography, CT and MRI plays a pivotal role in the selection and planning process; however, echocardiography remains the primary imaging modality used for patient selection, intra-procedural guidance, post-procedural assessment and long-term follow-up. The contribution that contemporary transthoracic and transoesophageal echocardiography make to the selection and planning of TAVI is described in this article

Opposite environmental gating of the experienced utility (‘liking’) and decision utility (‘wanting’) of heroin versus cocaine in animals and humans: implications for computational neuroscience

Background In this paper, we reviewed translational studies concerned with environmental influences on the rewarding effects of heroin versus cocaine in rats and humans with substance use disorder. These studies show that both experienced utility (‘liking’) and decision utility (‘wanting’) of heroin and cocaine shift in opposite directions as a function of the setting in which these drugs were used. Briefly, rats and humans prefer using heroin at home but cocaine outside the home. These findings appear to challenge prevailing theories of drug reward, which focus on the notion of shared substrate of action for drug of abuse, and in particular on their shared ability to facilitate dopaminergic transmission. Aims Thus, in the second part of the paper, we verified whether our findings could be accounted for by available computational models of reward. To account for our findings, a model must include a component that could mediate the substance-specific influence of setting on drug reward Results It appears of the extant models that none is fully compatible with the results of our studies. Conclusions We hope that this paper will serve as stimulus to design computational models more attuned to the complex mechanisms responsible for the rewarding effects of drugs in real-world contexts

Multimodality Imaging Markers of Adverse Myocardial Remodeling in Aortic Stenosis

Aortic stenosis (AS) causes left ventricular remodeling (hypertrophy, remodeling, fibrosis) and other cardiac changes (left atrial dilatation, pulmonary artery and right ventricular changes). These changes, and whether they are reversible (reverse remodeling), are major determinants of timing and outcome from transcatheter or surgical aortic valve replacement. Cardiac changes in response to AS afterload can either be adaptive and reversible, or maladaptive and irreversible, when they may convey residual risk after intervention. Structural and hemodynamic assessment of AS therefore needs to evaluate more than the valve, and, in particular, the myocardial remodeling response. Imaging plays a key role in this. This review assesses how multimodality imaging evaluates AS myocardial hypertrophy and its components (cellular hypertrophy, fibrosis, microvascular changes, and additional features such as cardiac amyloid) both before and after intervention, and seeks to highlight how care and outcomes in AS could be improved

An approach to the landscape analysis

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Synthesis and evaluation of enzyme inhibitors based on amino- and cyclopropane carboxylic acids

The coenzyme B12-dependent enzyme, glutamate mutase (E. C. 5.4.99.1), catalyses the reversible carbon-skeleton rearrangement of (2S)-glutamic acid to (25.35)-3-methylaspartic acid. Glutamate mutase is the first enzyme on the mesaconate pathway. A variety of glutamate and 3-methylaspartate analogues (which also include isotopically labelled molecules), were synthesised as molecular probes of the enzyme. Synthesis of stereospecifically labelled 3-ethylaspartic acid: (2S,3S)-[3'-C2H3], and (2S,3S)-[C2H2C2H3]-ethylaspartic acids were constructed using appropriately labelled iodoethane. (2S,3S)-2-Bromo-3-methylsuccinic acid was synthesised via the diazotization of (2S,3S)-3-methylaspartic acid, in the presence of bromide ion. (2S)-Methylsuccinic acid was synthesised by the catalytic hydrogenation of (2S,3S)-2-bromo-3-methylsucdnic acid. Biological studies of the synthesised compounds (including the labelled isotopomers) displayed no activity against glutamate mutase. 3-Methylaspartate ammonia-lyase, the second enzyme in the mesaconate pathway, catalyses the deamination of (2S,3S)-3-methylaspartic acid to mesaconic acid. A range of 1-substituted cyclopropane 1,2-dicarboxylic acids were synthesised using short efficient routes and were found to be good to potent inhibitors of 3-methylaspartase. X-ray crystallographic studies have determined the absolute stereochemistry. The mode of action of the most potent inhibitor, (1S,2S)-1-methylcyclopropane 1,2-dicarboxylic acid (20 mumol dm-3), is consistent with it acting as a transition state analogue for the central substrate deamination reaction catalysed by the enzyme. beta-Amino acids are constituents of many biologically active peptides. A general procedure for the synthesis of alpha-substituted-beta-amino acids has been developed. The synthesis involves a Baylis-Hillman amine catalysed conversion of methyl acrylate, with an appropriate aldehyde, to give the alpha-(hydroxyalkyl) acrylate. Bromination and subsequent azide displacement furnishes the azido alkene, which is catalytically hydrogenated, to furnish the beta-amino ester

The affective and neural correlates of heroin vs. cocaine use in addiction are influenced by environmental setting but in opposite directions

Previous studies have shown that individuals with heroin and cocaine addiction prefer to use these drugs in distinct settings: mostly at home in the case of heroin and mostly outside the home in the case of cocaine. Here we investigated whether the context would modulate the affective and neural responses to these drugs in a similar way. First, we used a novel emotional task to assess the affective state produced by heroin or cocaine in different settings, based on the recollections of male and female drug users. Then we used fMRI to monitor neural activity during drug imagery (recreating the setting of drug use) in male drug users. Consistent with our working hypothesis, the majority of participants reported a shift in the affective valence of heroin from mostly pleasant at home to mostly unpleasant outside the home (p<0.0001). The opposite shift was observed for cocaine, that is, most participants who found cocaine pleasant outside the home found it unpleasant when taken at home (p<0.0014). Furthermore, we found a double dissociation, as a function of drug and setting imagery, in BOLD signal changes in the left prefrontal cortex and caudate, and bilaterally in the cerebellum (all p's<0.01), suggesting that the fronto-striatal-cerebellar network is implicated in the contextualization of drug-induced affect. In summary, we report that the same setting can influence in opposite directions the affective and neural response to psychostimulants versus opiates in humans, adding to growing evidence of distinct substrates for the rewarding effects of these two drug classes